1. health and fitness
2. disease

Pouchitis and Pouch
Dys func tion
Hao Wu, MBa, Bo Shen, MDb,*
KEYWORDS
! Classification ! Complications ! Ileal pouch
! Inflammatory bowel disease
! Pouchitis ! Restorative proctocolectomy
Approximately 30% of patients with ulcerative colitis (UC) eventually require colectomy at some point in their disease course, despite advances in medical therapy.1
Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) has become
the surgical treatment of choice for most patients with UC who fail medical therapy or
develop dysplasia, and for most patients with familial adenomatous polyposis (FAP).
The main advantage of IPAA surgery includes re-establishment of gastrointestinal
continuity and improvement of health-related quality of life. However, the trade-off
of the procedure is its high risk for the development of inflammatory and noninflammatory complications, with cumulative pouch failure rates ranging from 4% to 10%.2–6
The most common causes for pouch failure are pelvic sepsis,7,8 followed by Crohn
disease (CD) of the pouch and chronic pouchitis.9
Pouchitis is one of the most challenging disorders in IPAA. This article updates the
information on diagnosis and treatment of pouchitis.
INCIDENCE AND PREVALENCE OF POUCHITIS
Pouchitis significantly affects patients’ quality of life and long-term surgical outcome.10
Reported cumulative frequencies of pouchitis 10 to 11 years after IPAA surgery range
from 23% to 46%.11–14 It is estimated that approximately 50% of patients who have
undergone IPAA surgery for UC develop at least 1 episode of pouchitis.15 The estimated
incidence within the first 12 months after ileostomy closure was as high as 40%, as reported in a clinical trial.16 In patients with pouchitis, 70% had the initial episode during
the first 12 months after ileostomy closure.17 As the incidence of inflammatory bowel
disease (IBD), including UC, seems to be increasing, the authors expect a growing
number of patients with pouchitis or other pouch disorders in clinical practice.
This work is partially supported by a grant from BMRP, Eli and Edyth Broad Foundation.
a
Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
b
Digestive Disease Institute-Desk A31, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH
44195, USA
* Corresponding author.
E-mail address: [email protected] (B. Shen).
Gastroenterol Clin N Am 38 (2009) 651–668
doi:10.1016/j.gtc.2009.07.002
0889-8553/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
gastro.theclinics.com
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ETIOLOGY AND PATHOGENESIS OF POUCHITIS
Pouchitis occurs almost exclusively in patients with underlying UC, not in patients with
FAP who undergo the same surgical procedure.18,19 It is generally believed that pouchitis results from alternations in luminal microflora (ie, dysbiosis), leading to abnormal
mucosal immune response in genetically susceptible hosts. Attempts have been
made to identify true pathogenic microbes. In a subset of patients with pouchitis,
pathogenic factors may be identified. A recent study showed that 18% of patients
seen in a specialty pouchitis clinic tested positive for Clostridium difficile toxins A or
B.20 Cytomegalovirus (CMV)21,22 and fungi (such as Candida albicans)23 have also
been implicated in pouchitis, particularly in patients with chronic antibiotic-refractory
pouchitis.
Although microbiological investigation of the bacterial communities in the gut failed
to demonstrate consistently the existence of pathogens in pouchitis, a large body of
evidence suggests that alteration in the bacteria community, ie, dysbiosis, of the
human gut likely plays a key role in the initiation and development of pouchitis. In
a culture-based study of fecal specimens in patients with UC pouches or FAP
pouches, viable sulfate-reducing bacteria were exclusively detected in pouches of
UC patients, but not in patients with FAP. Sulfate-reducing bacteria were detected
in higher numbers in active pouchitis than in those without a history of pouchitis,
past episode(s) of pouchitis, or on antibiotic therapy, and in patients with FAP.24
This particular group of bacteria was sensitive to antibiotic treatment.24 Gosselink
and colleagues25 analyzed bacteria content at the episode of pouchitis before and
during treatment with ciprofloxacin or metronidazole, and during pouchitis-free
periods, and found that, in the absence of inflammation, the pouch microbiota was
characterized by the presence of Lactobacilli and large numbers of anaerobes. During
pouchitis episodes, there was a decreased number of anaerobes, an increased
number of aerobic bacteria, lower numbers of Lactobacilli, and higher numbers of
Clostridium perfringens. In addition, hemolytic strains of Escherichia coli were
observed. Administration of metronidazole was shown to eradicate anaerobic microbiota including C perfringens, whereas treatment with ciprofloxacin inhibited the
growth of C perfringens and that of coliforms, including hemolytic strains of E coli.
Advances in molecular microbiology with 16S ribosomal RNA techniques have
provided a cornerstone of microbial taxonomy and made the assay of bacterial
composition in the gut community possible.26 In a case study, mucosa-associated
bacteria of the pouch were assayed using tissue biopsy samples at the time of colectomy, pouch construction, ileostomy closure, and postoperative routine pouch examination at 1, 3, and 12 months after ileostomy closure.26 The pouch microbiota were
similar to the normal colon microbiota except for the presence of clones with
sequences resembling those of the C perfringens group and Turicibacter. The bacterial composition differed between the 2 patients studied and the microbiota changed
with time, suggesting that the composition is not stable during the first year of ileostomy closure.26 Komanduri and colleagues27 studied pouch biopsy specimens from
5 patients with active pouchitis and 15 patients with normal pouches, using a fingerprinting technique. The study showed mucosa-associated microbiota patterns unique
to each individual. Moreover, specific bacterial amplicons were unique to active pouchitis mucosa: clostridial cluster XIVa, Enterobacteriaceae, and Streptococci were
associated with control pouches. The persistence of Fusobacter and enteric species
associated with the disease state was also shown.
Alterations in innate and adaptive mucosal immunity in the pouch and pouchitis have
been reported.28–33 An increased bacterial permeability was associated with duration of
Ileal Pouch Disorders
having a pouch with mucosal adaptive changes in an ex vivo study.28 UC patients
with backwash ileitis were shown to have impaired barrier function in the future
course of the IPAA.34 Toll-like receptors (TLR) serve an important immune and nonimmune function in human intestinal epithelial cells (IEC) by binding microbial signature
molecules and triggering innate and adaptive immune responses on stimulation.35
TLRs comprise a defense line against invading pathogens challenging the IEC layer.
TLRs can trigger the secretion of antibacterial peptides, and also link innate and
adaptive immune responses of the intestinal mucosa by attracting immune cells
from the lamina propria. An aberrant TLR expression pattern has been found in
IBD.36 An immunohistochemical study showed that TLR2 expression is up-regulated
in pouchitis and TLR4 expression is increased in the normal pouch and in pouchitis
compared with the normal ileum.37 Alterations in mRNA levels of TLR3 and TLR5
were present.38 TLR3 expression was decreased significantly, whereas TLR5 expression was increased significantly in normal pouch mucosa compared with normal ileal
mucosa.38 A combined carriership of the TLR9-1237C and CD14-260T allele seemed
to be associated with development of chronic pouchitis.39
Antimicrobial peptides produced from Paneth cells and other gut epithelial cells are
an important component of innate immunity in the intestinal tract.40–43 Paneth cells
synthesize and secrete several antimicrobial peptides, including lysozyme, secretory
phospholipase 2, and human a-defensins 5 and 6 (HD5 and HD6).42–45 The copy
number of HD5 mRNA was significantly decreased in the inflamed or noninflamed
pouch compared with the normal terminal ileum.46 Tissue mRNA copies of HD5
produced by Paneth cells and b (hBD-1, 2, 3)-defensins produced by gut epithelial cells
were increased in UC and FAP pouches immediately after surgery, compared with ileum
of controls. Initially, a- and b-defensin mRNAs were higher in UC pouches than in FAP
pouches. However, the defensin expression declined in UC and FAP pouch groups and
increased again slightly in pouchitis in patients with UC. FAP pouches without pouchitis
had strong expression of hBD-1, whereas all other defensins remained at low levels.47
As in IBD, adaptive immune mechanisms for pouchitis have been extensively
studied. For example, proliferation of immature plasma cells was increased in pouchitis.32–34,48 Proinflammatory cytokines, such as tumor necrosing factor-a, are released
mostly in the inflamed mucosa by macrophages and monocytes, leading to tissue
injury, and are considered to be involved as a secondary pathophysiologic mechanism
in pouchitis.33 The production of inflammatory mediators is increased including proinflammatory cytokines,47,49–52 cell adhesion molecules,53 platelet-activating factor,54
lipoxygenase products of arachidonic acids,55,56 vascular endothelial growth factor,56
proinflammatory neuropeptides, and other mediators.50,57–59 In general, UC pouches
expressed higher levels of inflammatory cytokines than FAP pouches.60 Abnormalities
in immunoregulatory cytokines such as IL-2, interferon-g,47,61 IL-4,47,61 and IL-1047
are also observed in pouchitis. Imbalance between proinflammatory and immunoregulatory cytokines has been described in patients with pouchitis.52 However, it is likely
that those abnormalities in mucosal adaptive immunity reflect activation of nonspecific
inflammatory cascade.50
The natural history of pouchitis may mimic that of UC, starting from an acute disease
process of bacterial etiology to chronic disease of persistent inflammation. There are
similarities in clinical presentations and immunologic abnormalities between chronic
pouchitis and UC. The presence of fecal stasis in the pouch, exposure to fecal contents,
and an increased microbial load of the pouch epithelia may result in inflammatory
changes leading to morphologic alterations in the ileal pouch mucosa mimicking
the colon epithelia in UC, namely colonic metaplasia.54,62 Colonic metaplasia, characterized by villous blunting, crypt cell hyperplasia, and colon epithelium-specific
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antigens such as human tropomyosin 5, may be associated with UC-like clinical
presentations.63 Colonic metaplasia seems to be associated with dysbiosis, particularly the presence of sulfate-reducing bacteria.64 It has been reported that mucosal
butyrate oxidation in pouchitis is similar to the findings in UC.65 An alteration in mucin
glycoproteins occurs in pouchitis similar to that seen in UC.66 It is possible that the
altered glycoproteins are more susceptible to enzymatic degradation by bacteria,
making the mucus barrier less effective.67
RISK FACTORS FOR POUCHITIS
Factors associated with pouchitis have been studied extensively as part of the investigation of the etiology and pathogenesis of pouchitis. In addition, the identification of risk
factors may have a direct impact on disease prevention and prognostication. Immunogenetic studies showed that genetic polymorphisms, such as those of the IL-1 receptor
antagonist68 and NOD2/CARD15,69 may increase the risk for pouchitis. Other reported
risk factors include extensive UC,70,71 the presence of backwash ileitis,17,70 precolectomy thrombocytosis,72 the presence of concurrent primary sclerosing cholangitis
(PSC)17,73,74 or arthralgia/arthropathy,75 seropositive perinuclear antineutrophil cytoplasmic antibodies (pANCA)14,76,77 or anti-CBir1 flagellin,14 being a nonsmoker,14,71,75
and the use of nonsteroidal anti-inflammatory drugs (NSAID).71,74 Acute antibioticresponsive pouchitis and chronic antibiotic-refractory pouchitis may represent different
disease processes associated with different etiopathogenetic pathways. As such,
acute and chronic pouchitis may be associated with different risk factors.71 In a recent
study of 238 patients with different phenotypes of pouchitis, antibiotic-responsive pouchitis developed in 37 pANCA-positive patients (22%) versus 6 pANCA-negative
patients (9%), and in 12 anti-CBir1–positive patients (26%) versus 31 anti-CBir1–negative patients (16%) during a median of 47 months of follow-up.14 In one report, patients
with backwash ileitis or PSC were associated with chronic pouchitis, but not with acute
pouchitis.17 Smoking was associated with acute pouchitis,14 whereas extraintestinal
manifestations,14 preoperative thrombocytosis, a long duration of IPAA,14 and postoperative surgery-related complications78 were reported to be associated with chronic
pouchitis. Smoking seems to be protective against the development of chronic pouchitis.79 These findings suggest that chronic pouchitis and UC may share similar pathogenetic pathways, as smoking has also been shown to be protective against progression
of UC.80 Patients with chronic antibiotic-refractory pouchitis, not acute pouchitis, were
associated with concurrent autoimmune disorders.81
Concurrent PSC is associated with an increased risk for backwash ileitis in patient
with UC. Furthermore, the prevalence of PSC among patients with UC needing proctocolectomy was higher than in patients with UC in general.74 Although PSC seems to
be a risk factor for pouchitis,73,74 particularly chronic pouchitis,82,83 orthotopic liver
transplantation together with post-transplant use of immunosuppressive agents
seems not to have a detrimental impact on the disease course of pouchitis.84,85
There have been discrepancies in the literature in reported risk factors associated
with pouchitis. With regard to inconsistency in the reported risk factors, there were intrainstitutional and interinstitutional variations. These variations could largely be due to
the difference in study design, sample size, diagnostic criteria used for pouchitis,
referral pattern, and statistical methods.
DIAGNOSIS OF POUCHITIS
Diagnosis of pouchitis is not always straightforward, because there are no specific
symptoms and signs. Patients with pouchitis have a wide range of clinical
Ileal Pouch Disorders
presentations, ranging from increased stool frequency, urgency, incontinence, nighttime seepage, to abdominal perianal discomfort. These symptoms, however, can be
present in other inflammatory and noninflammatory disorders of the pouch, such as
cuffitis, CD of the pouch, and irritable pouch syndrome. Therefore, the diagnosis of
pouchitis should not be solely dependent on symptom assessment. In addition,
severity of symptoms does not necessarily correlate with the degree of endoscopic
or histologic inflammation of the pouch.86,87 To complicate the matter even more,
the diagnosis of pouch disorders can resemble hitting a moving target, as the disease
process may not be static. For example, a patient may have typical pouchitis at 1
point, and may present CD of the pouch several months later. Therefore, a combined
assessment of symptoms, endoscopic, and histologic features is advocated for the
diagnosis and differential diagnosis of pouchitis.86,88 Pouch endoscopy provides the
most valuable information on the severity and extent of mucosal inflammation, backwash ileitis, CD of the pouch or cuffitis, and the presence of other abnormalities such
as polyps, strictures, sinuses, and fistula openings (Fig. 1). Although histology has
a limited role in grading the degree of pouch inflammation, it can provide valuable
information on some special features, such as granulomas, viral inclusion bodies
(for CMV infection), pyloric gland metaplasia (a sign of chronic mucosal inflammation),
and dysplasia. A diagnostic and treatment algorithm is proposed (Fig. 2).
Laboratory testing is often necessary as a part of the evaluation of patients with
pouch disorders, particular patients with chronic pouchitis. In patients with persistent
symptoms of pouchitis, celiac serology, salicylate screening, and microbiological
assays for C difficile and CMV may be performed.89 As most patients undergo
repeated or chronic antibiotic exposure, C difficile infection has been a growing
problem.20 Fecal assays of lactoferrin and calproprotectin have been evaluated for
the diagnosis and differential diagnosis of pouchitis. Quantitative90 and qualitative91
assays of lactoferrin have been used to distinguish pouchitis from normal pouches
or irritable pouch syndrome. Fecal lactoferrin may be used as an inexpensive
screening test for pouchitis.91,92 Fecal calprotectin assay had a sensitivity of 90%
and a specificity of 76.5% for the diagnosis of pouchitis in a recent study.93 However,
the diagnostic accuracy of these studies was assessed based on the comparison of
patients with pouchitis and patients with healthy pouches, whereas other inflammatory conditions such as cuffitis and CD of the pouch were not included in the prior
studies. Other laboratory tests, such as assays of fecal dimeric M2-pyruvate kinase94
and tissue proinflammatory cytokine gene scripts,95 may also be useful in distinguishing pouchitis from noninflammatory conditions of the pouch. However, laboratory
Fig.1. Endoscopy of inflammatory disorders of the pouch. (A) Pouchitis, inflammation of the
pouch body; (B) cuffitis, inflammation of the cuff; (C) Crohn disease of the pouch, ulcers at
the neoterminal ileum.
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Pouchitis Confirmed By Pouch Endoscopy
Ciprofloxacin or Metronidazole x 2 wks
No Response
Response
Infrequent
Relapse
Antx-responsive
Pouchitis
Antibiotics prn
Frequent
Relapse
Metronidazole or cipro x 2 wks
Response
Antx-dependent
Pouchitis
No Response
Antx-refractory
Pouchitis
- Probiotics
- Low-dose antibiotics
- Carbon microsphere?
Cipro+Metronidazole or
Rifaximin or
Tinidazole x4 wks
Oral or Topical 5ASAs/steroids/
Immunomodulators//biol
ogic therapy?
No Response
Evaluation for secondary causes
Fig. 2. Diagnostic and treatment algorithm of pouchitis.
tests should not replace pouch endoscopy as the first-line evaluation for the diagnosis
and differential diagnosis of pouchitis.
DIFFERENTIAL DIAGNOSIS OF POUCHITIS
There are overlaps in clinical presentations between a variety of inflammatory and
noninflammatory disorders of ileal pouches (see Fig. 1). Cuffitis is considered a variant
form of UC in the rectal cuff, particularly in patients with IPAA without mucosectomy.
Patients with cuffitis often present with bloody bowel movements, which seldom occur
in conventional pouchitis. When IPAA is constructed, there are 2 techniques to be
used for the pouch-anal anastomosis, hand-sewn versus staple techniques: the
hand-sewn IPAA with mucosectomy of the anal transition zone (ATZ) mucosa (or rectal
cuff mucosa) or a stapled IPAA at the level of the anorectal ring without mucosectomy
of the ATZ. To remove the rectal mucosa as completely as possible, a mucosectomy
with hand-sewn anastomosis is necessary. This technique normally takes longer and
has a high risk for postoperative functional problems related to seepage and incontinence due to anal canal manipulation. In contrast, the stapled anastomosis is easy to
perform and is less likely to result in functional and septic complications. The preservation of ATZ is meant to optimize anal canal sensation, eliminate sphincter stretching,
and preserve normal postoperative resting and squeeze pressures.5,7,8 However, to
allow transanal insertion of the stapler head, it is usually necessary to leave a 1- to
2-cm strip of rectal cuff/ATZ mucosa that is at risk for developing symptomatic inflammation (cuffitis) or even dysplasia.
Another common inflammatory disorder of the pouch is CD. It has been speculated
that IPAA surgery with change of bowel anatomy, anastomoses, and fecal stasis
creates a ‘‘CD-friendly’’ environment. CD of the pouch can occur after IPAA intentionally performed in a selected group of patients with Crohn colitis with no small intestinal
or perianal diseases96; CD is also inadvertently found in proctocolectomy specimens
of patients with a preoperative diagnosis of UC or indeterminate colitis. De novo CD of
the pouch, by far the most common form of CD, may develop weeks to years after
Ileal Pouch Disorders
IPAA for UC or indeterminate colitis. Clinical phenotypes of CD of the pouch can be
inflammatory, fibrostenotic, or fistulizing. There are symptoms and signs that would
suggest a diagnosis of CD, particularly fibrostenotic and fistulizing CD. It is critical
to differentiate NSAID-induced ileitis/pouchitis from CD ileitis, backwash ileitis from
diffuse pouchitis. Making a diagnosis of CD of the pouch often needs a combined
assessment of symptoms, endoscopy, histology, radiography, and sometimes examination under anesthesia.
Irritable pouch syndrome is a functional disorder in patients with IPAA.97 The
disease entity has a significant negative impact on health-related quality of life. There
are great overlaps in clinical presentation between irritable pouch syndrome and pouchitis. Contributing factors for the pathophysiology of irritable pouch syndrome
include visceral hypersensitivity, enterochromaffin cell hyperplasia,98 and proximal
small bowel bacterial overgrowth. Currently, irritable pouch syndrome is a diagnosis
of exclusion. Pouch endoscopy is the diagnostic modality of choice for to distinguish
between pouchitis and irritable pouch syndrome.
Patients with surgical complications (such as pouch sinus and pouch ischemia) can
present symptoms resembling those of pouchitis. Again, pouch endoscopy is considered the first-line diagnostic modality.
CLASSIFICATION OF POUCHITIS
The natural history of pouchitis is poorly defined. Patients with initial episodes of pouchitis almost uniformly respond to antibiotic therapy. However, relapse of pouchitis is
common. Among patients with acute pouchitis, 39% had a single acute episode that
responded to antibiotic therapy; the remaining 61% developed at least 1 recurrence.99
Approximately 5% to 19% of patients with acute pouchitis develop refractory or
rapidly relapsing forms of the disease.100–102 Pouchitis likely represents a disease
spectrum from an acute, antibiotic-responsive type to a chronic, antibiotic-refractory
entity. Based on the cause, disease duration, and activity, and response to medical
therapy, pouchitis can be categorized into: (1) idiopathic versus secondary, with
causes such as NSAID use and C difficile or CMV infection; (3) acute versus chronic,
with a cut-off time of 4 weeks of persistent symptoms; (4) infrequent episodes versus
relapsing versus continuous; and (5) responsive versus refractory to antibiotic
therapy.103
Classification based on the response to antibiotic therapy is useful in clinical practice.104 Analogous to the classification of UC according to the response to or dependency on corticosteroids, pouchitis can be classified into antibiotic-responsive,
antibiotic-dependent, and antibiotic-refractory pouchitis (Table 1).75 Pouchitis can
be diffuse or patchy. Based on the distribution of inflammation, pouchitis can be categorized into diffuse pouchitis, pouchitis with backwash ileitis, pouchitis with concurrent cuffitis, and segmental pouchitis. It is now clear that pouchitis can be seen as
a heterogeneous group, with different clinical phenotypes, that may be associated
with different risk factors, pathogenetic pathways, natural courses, and outcomes.
PROPHYLAXIS OF POUCHITIS
Some of the risk factors for pouchitis are modifiable, such as avoidance of the use of
broad-spectrum antibiotics or NSAIDs. It has been speculated that small bowel bacterial overload may be common, as there is no valve mechanism between the pouch and
distal small bowel, and pouch contents can easily reflux back to the segment of small
bowel. A diet with a low quantify of poorly absorbed short-chain carbohydrates may
reduce stool frequency in patients with or without pouchitis.105
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Table 1
Classification of pouchitis
Classification Based
on Disease Course
Classification Based
on Response to
AntibioticTherapy
Acute pouchitis
Antibiotic-responsive
pouchitis
Acute relapsing pouchitis
Chronic pouchitis
Antibiotic-dependent
pouchitis
Antibiotic-refractory
pouchitis
Classification
Based on Etiology
Idiopathic pouchitis (with
unidentified pathogens
or triggering factors)
Secondary pouchitis
- Clostridium difficile–
associated pouchitis
- Cytomegalovirus-associated pouchitis
- NSAID-induced
pouchitis
- Ischemic pouchitis
- Autoimmune pouchitis
Given that approximately 40% of patients develop pouchitis within the first 12
months after ileostomy closure,16 and that most patients who develop acute pouchitis
do so within the first year after IPAA,17,106 it is reasonable to consider primary or
secondary prophylaxis therapy, particularly in patients at risk.107 Efficacy and safety
of several probiotic agents have been evaluated. In a randomized trial of VSL#3 (containing viable lyophilized bacteria of 4 strains of Lactobacillus, 3 Bifidobacterium
species, and Streptococcus salivarius subsp thermophillus) for the primary prophylaxis of the initial episode of pouchitis, 2 of 20 patients (10%) in the study group
and 8 of 20 patients (40%) in the placebo group developed pouchitis within 12 months
after IPAA.16 Lactobacillus rhamnosus GG has also shown some efficacy in delaying
the first episodes of pouchitis.9,108 Although the efficacy of probiotic or prebiotic
agents in the primary prophylaxis remains to be further investigated, patients with
risk factors for pouchitis may try these agents.
In addition to primary prophylaxis, probiotic or antibiotic agents have been used as
a maintenance therapy for secondary prophylaxis in patients with relapsing pouchitis
or antibiotic-dependent pouchitis (see later discussion).
MANAGEMENT OF POUCHITIS
It is speculated that in most patients with pouchitis, the disease process is triggered
and maintained by bacterial causes from dysbiosis of commensal bacteria. However,
there are types of pouchitis that have identifiable pathogenic factors, such as C difficile,20 Candida albicans, and CMV infection, NSAID use, and pouch ischemia. Pathogen-targeted therapy is often effective.
There might be a new disease category named ‘‘autoimmune pouchopathy.’’81 The
patients often present with symptoms similar to ‘‘bacteria-associated’’ pouchitis, such
as increased stool frequency, cramps, and urgency. On endoscopy examination,
mucosal inflammation can be present in the pouch as well as a long segment of
afferent limb. Although there are currently no established diagnostic criteria, the diagnosis of autoimmune pouchopathy may be suspected if a patient has antibiotic-refractory pouchitis, concurrent autoimmune disorders (such as rheumatoid arthritis and
Ileal Pouch Disorders
Hashimoto thyroiditis), and serum autoantibodies. For patients with autoimmune
pouchopathy, treatment with oral budesonide or a low dose of immunomodulator
may be attempted.
The therapeutic effect of probiotics parallels the restoration of mucosal immune
response to altered microflora in the pouch.2,9,108–110 For example, probiotic-treated
patients were shown to have a significant increase in the percentage of regulatory
T cells.111 Changes in mucosa-associated bacteria in pouchitis were also reflected
by therapeutic administration of probiotic agents. Kuhbacher and colleagues23 conducted a double-blind, placebo-controlled trial to study the impact of a probiotic agent
containing viable lyophilized bacteria, comprising Lactobacilli, Bifidobacteria, and
Streptococci, on the dominant mucosa-associated bacteria from patients with chronic
pouchitis in remission induced by antibiotics. The mucosal microbiota was mainly detected within the epithelium and nearly all bacteria were affiliated with the Enterobacteriaceae group. Compared with the placebo group, an increase in Enterobacteriaceae
within the mucosa during the probiotic therapy was observed. Investigation of the
molecular species was performed with the construction of taxonomic group–specific
clone libraries. Using Proteobacteria/Enterobacteriaceae group–specific primers,
slight differences in terms of phylotypic composition were observed between the
placebo and probiotic groups. Enterobacter species and E coli were mainly identified.
Lactobacillus and Bifidobacterium clone libraries generated from the probiotic group
displayed a diverse spectrum of species in comparison with the 2 other experimental
groups (pretreatment remission group and placebo group). Analysis of the mucosaassociated microbiota using an electrophoretic fingerprinting technique showed that
the probiotic therapy increased the bacterial diversity in comparison with the patients
in the pretreatment remission and placebo administration groups.
Probiotics have been used as a maintenance therapy for patients with antibioticdependent pouchitis or relapsing pouchitis. A randomized trial of VSL#3 at a dose
of 6 g/d was conducted for the maintenance and secondary prophylaxis of relapse
of pouchitis, after remission was induced by oral ciprofloxacin (1000 mg/d) plus rifaximin (2000 mg/d). During the 9-month trial of 40 patients with relapsing pouchitis, 15%
in the probiotic group relapsed versus 100% in the placebo group.109 A separate
randomized trial of VSL#3 in patients with antibiotic-dependent pouchitis showed
that 17 of 20 patients (85%) in the VSL#3 group maintained clinical remission,
compared with remission in 1 of 16 patients (6%) in the placebo group.110 A metaanalysis of 5 randomized, placebo-controlled clinical trials was performed. Pooling
of the results from these trials yielded an odds ratio of 0.04 in the treatment group
in comparison with the placebo group. The benefit of probiotics in the management
of pouchitis after IPAA operation was confirmed by the meta-analysis.107 In addition,
high-dose probiotics have been used for treating pouchitis. In a study of the probiotic
agent, VSL#3, 3600 billion bacteria/d in treating mild pouchitis, 16 of 23 patients (69%)
were in remission after treatment.112
Routine use of probiotics for induction and maintenance therapy has generated
some controversy. However, some postmarket open-labeled studies reported
a much lower response rate. These outstanding results have been challenged by 2
recent postmarket open-labeled trials. In a study of 31 patients with antibiotic-dependent pouchitis treated with VSL#3 for maintenance therapy after 2 weeks of treatment
with ciprofloxacin, 25 patients (81%) had stopped the agent at 8 months, mainly
because of the lack of efficacy or development of adverse effects.113 Similar results
were reported in a separate open-labeled trial.114
Management strategies vary based on different types of pouchitis (see Fig. 2).9
Because most pouchitis is caused by bacteria, antibiotic therapy is the mainstream
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therapy. For antibiotic-responsive pouchitis, the first-line therapy includes a 14-day
course of metronidazole (15–20 mg/kg/d) or ciprofloxacin (1000 mg/d).115,116 A
randomized trial of ciprofloxacin and metronidazole showed that patients treated
with ciprofloxacin experienced significantly greater reductions in disease activity
scores and fewer adverse effects than those treated with metronidazole.116 A small
randomized trial of oral rifaximin 1200 mg/d versus placebo showed only a marginal
therapeutic benefit for active pouchitis.117 Diffuse pouchitis can be associated with
backwash ileitis, particularly in patients with concurrent PSC. Combination therapy
with ciprofloxacin and metronidazole for 28 days was shown to be effective in treating
backwash ileitis in a recent open-labeled trial.118 Other agents were reported in openlabeled trials, including tetracycline, clarithromycin, amoxicillin/clavulanic acid, doxycycline, budesonide enemas, alicaforsen enemas (an antisense inhibitor of intercellular
adhesion molecule-1), leukocytapheresis,119 AST-120 (a highly adsorptive, porous,
carbon microsphere),120 and dietary supplement of short-chain carbohydrates.
The gut-specific nonabsorbable antibiotic, rifaximin, may be a candidate for maintenance therapy in patients who need long-term antibiotics. In our recent study, 51
patients began maintenance therapy with rifaximin (median dose 200 mg/d); 33
(65%) maintained remission for 3 months. Of these 33 patients, 26 (79%) successfully
continued maintenance for 6 months after beginning maintenance, 19 (58%) successfully continued for 12 months, and 2 (6%) successfully continued for 24 months.121
Treatment of chronic antibiotic-refractory pouchitis is often challenging. In fact, this
phenotype of pouchitis is one of the most common causes for pouch failure. It is
important to investigate contributing causes related to failure of antibiotic therapy.
Secondary causes of refractory disease include use of NSAIDs, concurrent C difficile,20 CMV,21,22 or fungal23 infection, celiac disease and other autoimmune disorders,
cuffitis, and CD of the pouch. Chronic pouchitis can be associated with single or
multiple small or large inflammatory polyps. Large (>1 cm) pouch polyps can occasionally cause bleeding and can be dysplastic. Endoscopic polypectomy is feasible,
which may be helpful in controlling patients’ symptoms, in conjunction with medical
therapy.122 For patients without obvious causes, treatment options include a prolonged course of combined antibiotic therapy, mesalamine, corticosteroids, immunosuppressive agents, or even biologic therapy. In open-labeled trials, combined
agents of ciprofloxacin (1000 mg/d) with rifaximin (2000 mg/d),123,124 metronidazole
(1000 mg/d),125 or tinidazole (1000–1500 mg/d) for 4 weeks were reported to be effective.126 However, maintenance of remission in this group of patients after the induction
therapy with the dual antibiotic therapy remains challenging.127
Anti-inflammatory agents, immunomodulators, and biologic therapy have been
used to treat pouchitis. These agents include bismuth carbomer enemas, short-chain
fatty acid enemas, glutamine enemas, mesalamine enemas, 6-mercaptopurine, and
infliximab. In an open-labeled study of 20 patients with chronic refractory pouchitis,
oral budesonide 9 mg/d for 8 weeks induced remission in 15 (75%).128 Biologic agents
have been used in chronic pouchitis. Infliximab was studied for treating 10 patients
with chronic refractory pouchitis complicated by ileitis, using wireless capsule endoscopy. Clinical remission was achieved in 9 patients and endoscopic (with video
capsule endoscopy and pouch endoscopy) remission.129
In summary, management of pouchitis and other pouch disorders can be difficult.
One of the contributing factors for the complexity is the surgical component, which
may not be familiar to practicing gastroenterologists. A multidisciplinary approach
involving gastroenterologists and colorectal surgeons, together with a team of gastrointestinal pathologists and gastrointestinal radiologists, has been advocated. Few
institutions have even established subspecialty pouchitis clinics.10,130 The practice
Ileal Pouch Disorders
model has been feasible and effective in treating complicated pouch disorders in
a tertiary-care setting.
SUMMARY
Pouchitis is the most common long-term complication of IPAA, which represents
a spectrum of disease processes with different clinical phenotypes, risk factors, pathogenetic pathways, natural history, and prognosis. Pouch endoscopy is the most valuable tool for diagnosis and differential diagnosis. Although most patients with
pouchitis respond favorably to antibiotic therapy, antibiotic dependency and refractory disease have posed therapeutic challenges. Secondary causes of pouchitis,
such as C difficile infection, should be evaluated.
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